The overall objective of this UH2 application is to develop a potent, selective and orally active GABA-A ?5 Positive Allosteric Modulator (PAM) for the treatment of Mild Cognitive Impairment due to Alzheimer's Disease (MCI due to AD). There are currently no approved therapeutics for this indication making this an area of extremely high unmet need. There is strong support from preclinical AD models and human patients, particularly in this early stage of AD, that neuronal circuits in the hippocampus become excessively active contributing to neuronal pathology and brain dysfunction. AgeneBio's GABA-A ?5 PAM program represents a novel approach to addressing the excess hippocampal activity in this patient population at high risk for dementia. Recent preclinical and clinical studies using the atypical antiepileptic levetiracetam have supported the concept that reduction of hippocampal overactivity may be therapeutically beneficial. Ranging from research on age-associated memory impairment in rodents to clinical studies in patients with amnestic MCI, beneficial effects on key circuits in the medial temporal lobe/hippocampus and on memory performance have been demonstrated by treatment at low doses of levetiracetam that reduce hippocampal overactivity. The strong hippocampal localization of GABA-A ?5 receptors coupled with its role to control tonic inhibition make GABA-A ?5 PAMs well suited to reduce the excess hippocampal activity in MCI due to AD. Preclinical studies in rats with age-associated memory loss which show hippocampal overactivity demonstrate that selective GABA-A ?5 receptor PAMs are effective therapeutic agents to improve memory. Through ongoing medicinal chemistry efforts, AgeneBio's GABA-A ?5 PAM program is at a Discovery stage of lead optimization. The screening tree is well defined, all assays are in place, and compounds have advanced through the screening tree. Potent and selective GABA-A ?5 PAMS with good in vitro ADME properties and in vivo receptor occupancy have been identified. Additionally, several compounds demonstrate efficacy in vivo in a radial arm maze task in age-associated memory impaired rats. Improvements in blood brain barrier penetration and oral bioavailability are required in order to declare a lead compound ready for Development.